Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually occurring as an adverse effect of chemotherapy and radiotherapy treatment for cancer.
As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish white fibrin clot called a pseudomembrane. Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm and the oral ulcers can be severely painful. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well. The ulcers can also become infected, leading to septicemia and death, especially in immuno-compromised patients, which most cancer patients are.
Oral and gastrointestinal (GI) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of other patients. About half of all patients develop oral mucositis that becomes so severe that the patient's cancer treatment must be modified, compromising the prognosis. Thus, mucositis is a serious medical complication, preventing full oncology treatment plans from being implemented.
Treatment of mucositis to date has been mainly supportive. Oral hygiene is the mainstay of treatment—patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse. Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid irritants such as alcohol, citrus, and foods that are hot.
Medicinal mouthwashes may be used such as chlorhexidine gluconate or viscous lidocaine can be used for relief of pain. Palifermin (KEPIVANCE™) is an FDA approved human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have also been reported, including the use of cytokines and other modifiers of inflammation (e.g., IL-1, IL-11, TGF-beta3), amino acid supplementation (e.g., glutamine), vitamins, colony-stimulating factors, cryotherapy, and laser therapy.
Symptomatic relief of the pain of oral mucositis may be provided by barrier protection agents such as concentrated oral gel products (e.g. GELCLAIR™) CAPHOSOL™ is a mouth rinse that has been shown to prevent and treat oral mucositis caused by radiation and high dose chemotherapy. MUGARD™ is a FDA-approved mucoadhesive oral protectant designed to form a protective hydrogel coating over the oral mucosa while a patient is undergoing chemotherapy and/or radiotherapy cancer treatments to the head and neck. NEUTRASAL™ is an FDA-approved calcium phosphate mouth rinse that has been shown in an open-label, observational registry trial to prevent and reduce the severity of oral mucositis caused by radiation and high dose chemotherapy. The Mayo Clinic has been testing the antidepressant doxepin in a mouthwash to help treat symptoms, as well.
In 2011, the FDA approved EPISIL™ oral liquid for the management and relief of pain of oral lesions with various etiologies. EPISIL™ creates a lipid membrane that mechanically bonds to the oral cavity mucosa to coat and soothe inflammation and ulcerations, and blanket painful lesions.
In a 2012 randomized controlled pilot study involving pediatric patients, topical application of honey was found to reduce recovery time compared to benzocaine gel in grade 2 and 3 chemotherapy-induced oral mucositis to a degree that was statistically significant. In grade 3 oral mucositis, honey was as effective as a mixture of honey, olive oil and propolis, while both treatments were found to reduce recovery time compared to the benzocaine control.
Although there are promising palliative treatments, no drug has a mechanism of action designed to prevent the death of mucosal cells in the first place, and thus all treatments are symptomatic and not truly preventative.
Glutamine (abbreviated as GLN or Q) is one of the standard 20 amino acids. In human blood, glutamine is the most abundant free amino acid, with a concentration of about 500-900 μmol/l. It is not recognized as an essential amino acid, but may become conditionally essential in certain situations, including intensive athletic training, certain gastrointestinal disorders and in various disease states.
In catabolic states of injury and illness, glutamine becomes conditionally essential (requiring intake from food or supplements). Glutamine has been studied extensively over the past 10-15 years, and has been shown to be useful in treatment of injuries, trauma, burns, and treatment-related side effects of cancer, as well as in wound healing for postoperative patients. Glutamine is also marketed as a supplement used for muscle growth in weightlifting, bodybuilding, endurance, and other sports.
Glutamine is also known to have various effects in reducing healing time after operations. Clinical trials have revealed patients on supplementation regimens containing glutamine have improved nitrogen balances, generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes, and improved lymphocyte recovery and intestinal permeability (in postoperative patients), in comparison to those that had no glutamine within their dietary regimen, all without any side effects.
Glutamine-enriched diets have also been linked with maintenance of gut barrier function and cell differentiation, suggesting glutamine may help to protect the lining of the gastrointestinal tract or mucosa. People who have inflammatory bowel disease (ulcerative colitis and Crohn's disease) may not have enough glutamine, but the clinical trials to date have not been conclusive.
GLN has been shown to be effective in preventing mucositis, but the literature has provided inconsistent reports as to its efficacy. Since the initial reports, it has been discovered that sugars administered together with glutamine improves cellular uptake by about three orders of magnitude. U.S. Pat. No. 7,041,651 for example shows that 30-50% monosaccharide or disaccharide or combinations thereof increases GLN uptake by 1000 fold when measured in CaCo-2 cells (a caucasian colon adenocarcinoma cell line) in vitro. Thus, early formulations may have failed for lack of uptake and/or degradation, since many were formulated without sugars, e.g., in saline, and since glutamine is subject to enzymatic and chemical hydrolysis. Unfortunately, only a single complex mixture containing 30% sucrose plus a number of other ingredients was tested in U.S. Pat. No. 7,041,651. Therefore, the scope and concentration of carbohydrates that actually exhibit carrier/uptake function remains unknown.
One glutamine formulation was approved as an orphan drug in 2004. NUTRESTORE™ is a powdered glutamine approved for an oral dosage in 8 ounces of water of 5 grams six times daily in combination with recombinant human growth hormone for the treatment of short bowel syndrome. No pharmacokinetic data were provided and a therapeutic concentration has not been established. The package insert does state, however, that single doses of 20-22 g/kg, 8-11 g/kg and 19 g/kg were lethal in mice, rats and rabbits respectively. It is possible and even likely that large doses are provided to compensate both for a short half life and limited uptake, and such large doses were accompanied by common side effects such as urge to empty bowels, gas, abdominal pain, vomiting, and hemorrhoids.
Another early attempt to formulate a useful pharmaceutical is described in U.S. Pat. No. 5,438,075 and known as “SAFORIS™.” This drug was formulated as a suspension containing 500 mg/ml glutamine, 30% sucrose, 2.5% glycerin, 2.8% sorbitol, 0.04% citric acid, 0.36% NaPO4, 0.16% cellulose and carboxymethylcellulose, 0.04% carrageenan, and 0.04% xanthum gum. An NDA for SAFORIS™ was submitted in 2006, but was not granted due to concerns about adverse cariogenic effects of sucrose, as well as diabetic side effects of frequent ingestions of sucrose.
Thus, what is needed in the art are better treatment regimes and better formulations for delivery of glutamine for the prevention and/or treatment of mucositis and other epidermal or gastrointestinal disorders, and for the general nutritional support of cells under stress.